Many times each day, we see food or representations of food and evaluate whether or not the food looks good to us. If it does, we then balance external factors, such as the social situation or time of day, against internal signals about our hunger state in order to decide what and when to eat. However, recent functional magnetic resonance imaging (fMRI) studies suggest that internal signals, such as hormones regulating appetite and satiety, govern our food intake in part by acting on neural circuits to affect whether a given food appears appetizing at that moment. Through her K23 award, Dr. Schur has demonstrated that, at baseline, photographs of food perceived to be "fattening" activate brain regions involved in appetite and reward processing, including the hypothalamus, nucleus accumbens, and orbital frontal cortex. This activity is potently reduced by food intake, suggesting that it reflects underlying brain mechanisms involved in satiety. We now propose to study the mechanism of these changes in brain activity by asking if they are directly related to the action of glucagon-like peptide-1 (GLP-1), a satiety signal. GLP-1 is released by cells in the gut in response to nutrients, suppressing food intake, and its actions can be blocked by a GLP-1 receptor antagonist, exendin-[9-39]. In 2 randomized, controlled, crossover studies, we will assess whether exendin-[9-39] infusions reverse GLP-1-mediated effects on food intake and on brain response to visual food cues. Our scientific aims are 1) To establish a dose-response curve for the effect of exendin-[9-39] to block GLP-1-mediated satiety in humans, and 2) to test whether endogenous GLP-1 signaling is required for the effect of a meal to reduce brain response to visual food cues in humans. We hypothesize that exendin-[9-39] will diminish the effect of a meal in suppressing subsequent food intake and in reducing activation to visual food cues in reward pathways. Determining the extent to which the experience of satiety arises from a decrease in the reward value of food is fundamentally important to understanding human feeding behavior. In addition, this promising line of research is directly relevant to some of the most pressing public health issues of our time: obesity and overnutrition. We hope that investigating mechanisms affecting our perception of satiety at the most basic level will eventually result in novel behavioral or pharmacologic strategies for obesity prevention and treatment. PUBLIC HEALTH RELEVANCE: Obesity and the health complications of obesity are one of the most important public health concerns of our times. This research may suggest avenues for behavioral or pharmacologic treatment to aid in achieving and maintaining weight loss.